Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

C215Fab-IL-2 fusion protein, with full IL-2 and antigen binding activity, was produced in E. coli at high level (>50 mg/l). When co-administered with Fab-superantigen fusion protein (C215Fab-SEA) in mice strong and sustained T cell activation was observed. Combination treatment of mice carrying B16 melanoma transfected with C215 antigen was also more efficient than using C215Fab-SEA (p<0.01) or C215Fab-IL-2 alone (p<0.001). In a long-term survival experiment 5/12 mice having received combination treatment 5 days after i.v. inoculation of B16 cells survived >85 days. Improved therapeutic efficacy correlated with increased tumor infiltration by activated CD25+ T cells, indicating a T cell mediated mechanism.
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PMID:Treatment with tumor-reactive Fab-IL-2 and Fab-staphylococcal enterotoxin A fusion proteins leads to sustained T cell activation, and long-term survival of mice with established tumors. 1053 68

Of the past several years progress in understanding TCR signal transduction has led to the discovery of new kinases, adapter molecules and multiple signaling pathways. The study of molecules such as LAT, SLP-76, FYB, SKAP-55 and VAV have revealed multiple mechanisms with which to control the activation of downstream signaling pathways through RAS, PLC gamma-1 and ERK/MAPK. Signaling through SLP-76 can play a role in TCR-induced cytoskeleton changes through activation of effector molecules in the RAC/RHO-family of GTPases. In addition, SLP-76 through its association with FYB/FYN-T appears to play a role in IL-2 gene transcription following TCR activation. Finally, these newly identified adaptor molecules, such as LAT, may be crucial in T-cell activation by enhancing the recruitment of critical kinases to glycolipid-enriched microdomains of the activated T-cell receptor complex.
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PMID:Signaling scaffolds in immune cells. 1064 61

Adoptive immunotherapy as a new approach has been used to treat advanced carcinoma for almost ten years, and gained some good results. However, the application of this method is largely restricted by the side effects along with high dose of IL-2 and lack of sufficient amount of LAK cells. Mycobacterial Polysaccharides (MPS) and anti-CD3 antibodies (CD3Ab) have been demonstrated to be effective immunologic modifiers capable of proliferating lymphocytes and increasing cytotoxity against tumor cells. In this article we discussed the effects of MPS and CD3Ab on proliferation and cytotoxity against HEP-2 cells of LAK cells. Our results showed that: 1. MPS group (incubating IL-2 2 x 10(5)/L plus MPS 0.4 mg/L) or CD3 group (IL-2 1 x 10(6)/L plus CD3Ab 4 mg/L) were more proliferative than LAK group (only incubated with IL-2 1 x 10(6)/L). MPS group is the most proliferative in the three groups, P < 0.05. 2. Cytotoxity against HEP-2 in MPS or CD3 group was also better than in LAK group. CD3 group could maintain good cytotoxity in the longest period. These results could provide guidance for adoptive immunotherapy assisted by MPS or CD3Ab.
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PMID:[The study of effects of immunologic modifier on proliferation and cytotoxicity against HEP-2 of LAK cells in vitro]. 1074 94

Intrathymic injection of alloantigens appears to be the most efficient route to induce alterations of T cell reactivity. In the present study, we explored the modifications of Vbeta8.1, 8.2 T cell population and T cell reactivity in the thymus and in the spleen induced by intrathymic injection of staphylococcal enterotoxin B to adult mice. Vbeta8 antigen expression was investigated by flow cytometry analysis. T Cell reactivity was studied in vitro by the proliferative response to SEB. SEB induced a significant reduction in the percentage of mature Vbeta8+ T cells in the thymus (days 7-14), and in the spleen (days 7-28). Interestingly, this depletion occurs in the CD4- CD8+ cells in the thymus whereas in the CD4+ CD8- cells in the spleen. In parallel, the proliferative response to SEB but not to SEA was significantly decreased in the thymus on days 7 and 14, and in the spleen from day 7 to day 28. Moreover, this unresponsiveness was more pronounced in the spleen than in the thymus. Anergy was SEB-specific and fully reversed by exogenous IL-2. SEB injected intrathymically induced significantly more pronounced and more durable T cell alterations than intraperitoneal and subcutaneous injections. This may be related to the observation that after i.t. injection, SEB was detected both at a higher amount and for a longer period in the central and peripheral compartments. Our results clearly demonstrate that the intrathymic route is definitely the most efficient to induce not only thymic but also peripheral pivotal immune alterations in our model.
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PMID:T cell deletion and unresponsiveness induced by intrathymic injection of staphylococcal enterotoxin B. 1083 9

Our previous studies have shown that the enzymatic activities of Neu-1, an endogenous sialidase encoded in the murine MHC, are involved in promoting IL-4 synthesis by naive CD4(+)T cells. Our present studies have characterized responsible sialoconjugate targets of Neu-1 and questioned possible biochemical mechanisms responsible for their regulatory influences on IL-4 gene expression. These studies determined that treatment of T cells with the naturally occurring ganglioside GM3 inhibited the production of IL-4 without affecting the production of IL-2. An analysis of IL-4-primed CD4(+)T cells further demonstrated that GM3 treatment specifically inhibited the restimulated production of IL-4, IL-5 and IL-13, without inhibiting the production of IL-2 and IFN-gamma. The inhibitory effects of GM3 could be overcome by treatment with thapsigargin or ionomycin, suggesting ganglioside regulation occurs upstream of activation-induced calcium mobilization. GM3 treatment attenuated the level of calcium influx following CD3epsilon crosslinking, and CD4(+)T cells from Neu-1-deficient B10.SM strain mice (neu-1(a)and IL-4-deficient) expressed reduced levels of intracellular calcium following activation. Our results indicate that activities by membrane gangliosides can influence the cytokine programs in CD4(+)T cells, possibly through the modulation of calcium responses induced by T cell activation.
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PMID:Ganglioside control over IL-4 priming and cytokine production in activated T cells. 1088 Feb 42

TCR- but not CD2-triggered IL-2 production is p56(lck) dependent. To test the hypothesis that p59(fyn), a second src-family protein tyrosine kinase (PTK) expressed in T lymphocytes, might be an essential upstream component of the CD2 signaling pathway, we generated human (h) CD2 transgenic (tg) fyn(+/+) and fyn(-/-) mice. Clustering of hCD2 molecules on resting peripheral T lymphocytes results in Ca(2+) mobilization, activation of MAPK and cellular proliferation. In contrast, in the absence of p59(fyn), these CD2-initiated activities are markedly reduced, while TCR-triggered proliferation is unaffected. Several CD2 pathway components regulated by p59(fyn) have been identified including phospholipase C-gamma1 (PLC-gamma1), Vav, protein kinase C-theta isoform (PKC-theta), docking protein (Dok), focal adhesion kinase (FAK) and Pyk2. Decreased inducible PKC-theta catalytic activity and Vav phosphorylation likely account for diminished p38 and JNK activation in hCD2tg fyn(-/-) mice. Moreover, deficiency in fyn-dependent PLC-gamma1 catalytic activity may contribute to reduced PKC-alpha-dependent ERK activation. Of note, CD2-dependent Dok but not linker from activated T cells (LAT) tyrosine phosphorylation requires p59(fyn). Furthermore, that FAK and Pyk2 are target substrates implies that p59(fyn) may be an important regulator of T cell adhesion as well. Collectively, these data identify p59(fyn) as a key PTK in CD2-mediated activation of mature T lymphocytes.
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PMID:A critical role for p59(fyn) in CD2-based signal transduction. 1109 70

IL-2, first identified as a T cell growth factor, has been proven to activate many cell types including polymorphonuclear neutrophils (PMN3). However, the mechanisms involved in PMN activation, especially the signaling pathways used by the IL-2R, are currently unknown. Here we demonstrate that IL-2 has the ability to induce protein tyrosine kinases in human PMN, and we provide the first evidence that lyn kinase is activated and physically associated with MAP kinase/ERK1. Co-immunoprecipitation experiments with anti-IL-2Rbeta and Western blotting with anti-p53/56lym revealed that lyn protein was present in IL-2R precipitates and that the association of lyn with IL-2Rbeta was markedly elevated by IL-2 stimulation. Furthermore the activity of lyn kinase, evaluated by an in vitro kinase assay with enolase as a substrate, increased following IL-2 stimulation. Another important finding was that, upon IL-2 activation, MAPK/ERK1 was also phosphorylated in PMN. A direct association between lyn and ERK1 was initially demonstrated by co-immunoprecipitation/Western blotting and then definitively proven by the use of a GST-ERK1 fusion protein. We showed that ERK1 binds lyn only in IL-2 stimulated PMN, but not in unstimulated PMN. These results suggest that IL-2 can promote the association of lyn protein tyrosine kinase with IL-2Rbeta as well as the direct binding of MAPK/ERK1 to lyn. The signaling pathway utilized by human PMN in response to IL-2 may thus involve the association of lyn with IL-2Rbeta and the activation process also triggers the recruitment and activation of a specific ERK.
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PMID:IL-2 induces the association of IL-2Rbeta, lyn, and MAP kinase ERK-1 in human neutrophils. 1113 Nov 53

The repeated injection of bacterial superantigens (SAg), such as staphylococcus enterotoxin (SE) A or B, has been shown in mice to induce a state of unresponsiveness characterized by the lack of secretion of Th1 lymphokines, such as IL-2 and IFN-gamma, following subsequent SAg challenge. We made the observation, in vivo as well as in vitro, that unresponsiveness to SAg could be transferred from SEA- to SEB-reactive T cells (and reversibly from SEB- to SEA-specific T cells) in C57BL/6 mice but not in BALB/c mice. Since C57BL/6 mice, unlike BALB/c mice, possess TCR V(beta)3+ and V(beta)11+ T cells able to react with both SEA and SEB, we hypothesized that SAg-unresponsive V(beta)3(+) and V(beta)11+ T cells could mediate linked suppression of other SAg-reactive T cells. To analyze further this possibility, spleen cells from BALB/c mice made unresponsive to SEB were tested for their capacity to suppress the response of normal BALB/c cells to SEB. The production of both IFN-gamma and IL-2 following SEB stimulation was greatly impaired in co-cultures containing CD4(+) T cells, but not CD8(+) T cells, isolated from unresponsive animals. In vivo, the production of both IFN-gamma and IL-2 responses to SEB was dramatically reduced in animals adoptively transferred with unresponsive spleen cells. This suppression was abrogated in recipients injected with neutralizing anti-IL-10 antibodies. Moreover, in animals made unresponsive to SEB, SAg-reactive CD4(+) T cells were found to express high levels of CTLA-4, a molecule recently described to play an essential role in the suppressive function of regulatory T cells. Taken together these results demonstrate that the repetitive injection of SAg induces the differentiation of regulatory CD4(+) T cells capable of suppressing SAg-reactive naive T cells.
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PMID:Chronic exposure to superantigen induces regulatory CD4(+) T cells with IL-10-mediated suppressive activity. 1128 82

In this study, the ability of purified bovine gammadelta T cells in vitro to be activated by superantigens (SAg) was investigated. Freshly isolated WC1(+) gammadelta T cells, in the presence of autologous glutaraldehyde-fixed or gamma-irradiated antigen presenting cells (APC) and IL-2, were incubated with staphylococcal enterotoxins A and B (SEA and SEB), and toxic shock syndrome toxin-1 (TSST-1). Both a proliferative response and the expression of particular T cell receptor genes of the gamma variable (TCR Vgamma) repertoire family were induced. Genes encoding TCR Vgamma1 and TCR Vgamma2 family, but not TCR Vgamma5 were detected. The cells also expressed cytokine transcripts, namely, those of IL-12, IFN-gamma and TNF-alpha, but not IL-2, IL-4, IL-6, IL-7 and IL-10. The activation and proliferation of freshly isolated gammadelta T cells by non-processed antigens required two signals, one originating from the APC and a second dependent on exogenous IL-2. Our results show that purified bovine WC1(+) gammadelta T cells could be driven to proliferate and to express a particular TCRVgamma profile in response to superantigen activation. The possible implication of cytokines expressed by bovine gammadelta T cells in immunopathogenesis is discussed.
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PMID:Purified bovine WC1+ gamma delta T lymphocytes are activated by staphylococcal enterotoxins and toxic shock syndrome toxin-1 superantigens: proliferation response, TCR V gamma profile and cytokines expression. 1137 2

Bacterial superantigens trigger an excessive, Th1-cytokine response leading to toxic shock. We designed a peptide antagonist that inhibits SEB-induced expression of human genes for IL-2, IFN-gamma, and TNF-beta, cytokines that mediate shock. The peptide antagonist shows homology to a beta-strand-hinge-alpha-helix domain that is conserved structurally in superantigens produced by Staphylococcus aureus and Streptococcus pyogenes yet remote from known binding sites for the major histocompatibility class II molecule and T-cell receptor. For Th1-cell activation, superantigens depend on this domain. The peptide protected mice against lethal challenge with SEB or SEA. Moreover, it rescued mice undergoing toxic shock. Surviving mice rapidly developed broad-spectrum, protective immunity, which rendered them resistant to further lethal challenges with different staphylococcal and streptococcal superantigens. Thus, the lethal effect of superantigens, mediated by Th1 cytokines, can be blocked with a peptide antagonist that inhibits their action at the top of the toxicity cascade, before activation of T cells takes place.
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PMID:Superantigen antagonist blocks Th1 cytokine gene induction and lethal shock. 1140 77


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